NIH Discovery Brings Stem Cell Therapy for Eye Disease Closer to the Clinic

Scientists at the National Eye Institute (NEI), part of the National Institutes of Health, report that tiny tube-like protrusions called primary cilia on cells of the retinal pigment epithelium (RPE)—a layer of cells in the back of the eye—are essential for the survival of the retina’s light-sensing photoreceptors. The discovery has advanced efforts to make stem cell-derived RPE for transplantation into patients with geographic atrophy, otherwise known as dry age-related macular degeneration (AMD), a leading cause of blindness in the U.S.  The study appears in the January 2 Cell Reports.

“We now have a better idea about how to generate and replace RPE cells, which appear to be among the first type of cells to stop working properly in AMD,” said the study’s lead investigator, Kapil Bharti, Ph.D., Stadtman Investigator at the NEI. Bharti is leading the development of patient stem cell-derived RPE for an AMD clinical trial set to launch in 2018.

In a healthy eye, RPE cells nourish and support photoreceptors, the cells that convert light into electrical signals that travel to the brain via the optic nerve. RPE cells form a layer just behind the photoreceptors. In geographic atrophy, RPE cells die, which causes photoreceptors to degenerate, leading to vision loss.

Bharti and his colleagues are hoping to halt and reverse the progression of geographic atrophy by replacing diseased RPE with lab-made RPE. The approach involves using a patient’s blood cells to generate induced-pluripotent stem cells (iPSCs), cells capable of becoming any type of cell in the body. iPSCs are grown in the laboratory and then coaxed into becoming RPE for surgical implantation.

Attempts to create functional RPE implants, however, have hit a recurring obstacle: iPSCs programmed to become RPE cells have a tendency to get developmentally stuck, said Bharti. “The cells frequently fail to mature into functional RPE capable of supporting photoreceptors. In cases where they do mature, however, RPE maturation coincides with the emergence of primary cilia on the iPSC-RPE cells.”

The researchers tested three drugs known to modulate the growth of primary cilia on iPSC-derived RPE. As predicted, the two drugs known to enhance cilia growth significantly improved the structural and functional maturation of the iPSC-derived RPE. One important characteristic of maturity observed was that the RPE cells all oriented properly, correctly forming a single, functional monolayer. The iPSC-derived RPE cell gene expression profile also resembled that of adult RPE cells. And importantly, the cells performed a crucial function of mature RPE cells: they engulfed the tips of photoreceptor outer segments, a pruning process that keeps photoreceptors working properly.

By contrast, iPSC-derived RPE cells exposed to the third drug, an inhibitor of cilia growth, demonstrated severely disrupted structure and functionality.

As further confirmation of their observations, when the researchers genetically knocked down expression of cilia protein IFT88, the iPSC-derived RPE showed severe maturation and functional defects, as confirmed by gene expression analysis. Tissue staining showed that knocking down IFT88 led to reduced iPSC-derived RPE cell density and functional polarity, i.e., cells within the RPE tissue pointed in the wrong direction.

Bharti and his group found similar results in iPSC-derived lung cells, another type of epithelial cell with primary cilia. When iPSC-derived lung cells were exposed to drugs that enhance cilia growth, immunostaining confirmed that the cells looked structurally mature.

The report suggests that primary cilia regulate the suppression of the canonical WNT pathway, a cell signaling pathway involved in embryonic development. Suppression of the WNT pathway during RPE development instructs the cells to stop dividing and to begin differentiating into adult RPE, according to the researchers.

The researchers also generated iPSC-derived RPE from a patient with ciliopathy, a disorder that causes severe vision loss due to photoreceptor degeneration. The patient’s ciliopathy was associated with mutations of cilia gene CEP290. Compared to a healthy donor, iPSC-derived RPE from the ciliopathy patient had cilia that were smaller. The patient’s iPSC-derived RPE also had maturation and functional defects similar to those with IFT88 knockdown.

Further studies in a mouse model of ciliopathy confirmed an important temporal relationship: Looking across several early development stages, the RPE defects preceded the photoreceptor degeneration, which provides additional insights into ciliopathy-induced retinal degeneration.

The study’s findings have been incorporated into the group’s protocol for making clinical-grade iPSC-derived RPE. They will also inform the development of disease models for research of AMD and other degenerative retinal diseases, Bharti said.

This work was supported by the NEI intramural research program and the NIH Common Fund’s Regenerative Medicine Program.

Biotech Agreement Advances Molecular Envelope Technology (MET) to develop a Cannabis-based Drops to Treat Glaucoma

NEMUS Bioscience, Inc. announced that the company has signed a development agreement with Nanomerics Ltd. of the United Kingdom, to develop a topical ocular formulation of tetrahydrocannabinol-valine-hemisuccinate (THCVHS), the prodrug of THC, which is the active component of Nemus drug candidate NB1111 being developed for the treatment of glaucoma. The aim of the agreement is to conduct initial studies assessing the preparation of clinical-grade eye drops using the patented Molecular Envelope Technology (MET) developed by Nanomerics. Work under the agreement will commence on a future date to be determined by Nemus in connection with its development plans and corporate objectives.

“Historically, it has been challenging to formulate hydrophobic, or fat-soluble, cannabinoid molecules for efficient and predictable entry into the body, especially the eye,” stated Brian Murphy, M.D., M.B.A., Nemus CEO and Chief Medical Officer. “Nemus has found the MET technology profile to be supportive of the work performed to-date using the more hydrophilic THCVHS which was designed to cross physiologic barriers more efficiently. Developing this formulation is an important step before conducting human studies.”

“Nanomerics looks forward to working with Nemus on creating medicines that address the medical need for the improved treatment of glaucoma. Nemus, as the only cannabinoid company we are aware of with a complement of prodrugs and analogues of THC and CBD, is uniquely placed to potentially develop these for use in multiple forms of ocular disease,” commented Professor Andreas Schätzlein, co-founder and CEO of Nanomerics. Nanomerics’ CSO and co-founder Professor Ijeoma Uchegbu explained, “We feel that the MET platform will help NB1111 deliver in the clinic what has already been shown in several animal studies. Namely, penetration into multiple chambers of the eye, a non-opaque eye drop, and a neutral-pH at delivery to lower the risk of eye irritation which is an adverse event seen with some established therapies in glaucoma.”

Dr. Murphy noted, “Should we find success in formulating NB1111 using Nanomerics’ MET, we could also examine its application using our proprietary Nemus ophthalmic analogue of CBD (NB2222). Our company objective is to establish strategic partnerships utilizing a diverse cannabinoid-based ocular platform to address multiple types of eye disease.”


FAU and Sancilio & Company, Inc. Collaborate to Further Develop Treatment for Retinitis Pigmentosa

Researchers from Florida Atlantic University are collaborating with scientists from Sancilio and Company, Inc., in Riviera Beach, Fla., to begin a new research project aimed at finding a treatment for patients afflicted by Retinitis Pigmentosa (RP). RP is an inherited disease that causes severe progressive vision impairment and blindness. The disease is recognized as the leading cause of inherited blindness that affects approximately 1 in 4,000 people and can cause blindness as early as within the first year of life.

“There are currently no treatments available for this devastating progressive and degenerative eye disorder,” said Frederick Sancilio, Ph.D., president of Sancilio & Company, Inc. “By combining our knowledge, resources and expertise with neuroscientists from Florida Atlantic University we are hopeful that we will be able to further develop a treatment to halt this disease.”

Prior preclinical studies performed by scientists at Sancilio and Company, Inc. have demonstrated the potential therapeutic effect of SC412, an investigational drug that the company is currently developing for the treatment of this condition. In partnership with neuroscientists in FAU’s Charles E. Schmidt College of Science and Charles E. Schmidt College of Medicine, Sancilio and Company, Inc. will test the therapeutic effects of SC412 in a validated animal model for RP. In addition, the project also will investigate different formulations to define the best and most convenient route of administration.

Wen Shen, Ph.D., a neuroscientist, associate professor of biomedical science in FAU’s College of Medicine and a faculty member in FAU’s Brain Institute who has expertise in retinal physiology, will spearhead evaluating the new drug in the animal model. Her laboratory will carry out the initial testing of SC412 on the animal model for RP, investigating the effectiveness and safety of the compound and gathering the basic information for a preclinical trial.

“Having positive results from these experiments will be a significant step closer to testing this molecule in human studies in the near future,” said Sancilio.

FAU neuroscience faculty members are tackling many of the cutting-edge questions in neuroscience through the integration of multiple disciplines, different model systems and a broad spectrum of technologies.

JCyte Completes Enrollment For Phase I/IIa Safety Trial

Company is poised to begin phase IIb efficacy trial in 2017

California-based regenerative medicine company jCyte has completed enrollment in a phase I/IIa trial to study the safety of its stem cell therapy candidate for retinitis pigmentosa (RP). The trial included 28 patients with advanced RP, eight of whom have completed the one-year study. Early safety results have been promising.

“We have successfully completed four DSMB (Data Safety Monitoring Board) reviews,” said jCyte co-founder Henry Klassen, MD, PhD. “So far, trial participants have had no significant side effects, with good tolerance of the injected cells. We are quite gratified by the results.”

The company’s investigational therapy, called jCell, uses injected retinal progenitor cells, which are intended to rescue dying retinal cells (rods and cones) and possibly regenerate new ones. The non-surgical treatment requires a single intravitreal injection, which can be performed in an ophthalmologist’s office under local anesthesia.

Retinitis pigmentosa is an incurable eye disease that destroys retinal cells and ultimately leads to blindness. It is a genetic condition that generally strikes people in their teens. Many patients are blind by the time they are 40. Worldwide, almost 1.5 million people suffer from RP, making it the leading cause of inherited blindness. Currently, there are no effective treatments.

The ongoing trial is being conducted at the Gavin Herbert Eye Institute at the University of California, Irvine and Retina Vitreous Associates in Los Angeles and has received significant support from the California Institute for Regenerative Medicine (CIRM).

As the safety trial winds up, jCyte has begun planning a phase IIb trial, which they hope to begin in 2017.

“I look forward to the next stage of development towards commercialization,” says jCyte CEO Paul Bresge. “We never lose sight of our singular goal: to ultimately deliver this much-needed therapy to patients.”

Bresge encourages RP patients who wish to participate in future trials to visit

Cannabinoid-Based Therapeutics may present opportunity in Reducing Intraocular Pressure: Study

Data from a preclinical study presented last week at the 2016 AAPS National Meeting demonstrated significant data concerning the effects of a cannabinoid-based drug in lowering the effect of Intraocular Pressure (IOP).

The abstract, “Effect of single versus multiple day regimen of Δ9 -THC-valine-hemisuccinate (THCVHS) on the intra-ocular pressure (IOP) lowering activity in normotensive rabbits” (abstract # 30W0830), reports data comparing the prodrug of tetrahydrocannabinol (THCVHS) also known as NB1111 (Nemus Bioscience), to established glaucoma therapies of Pilocarpine and Timolol, as well as standard Δ9 -THC in both emulsion and solid lipid nanoparticle (SLN) eye drops. All studies were conducted in a normal, non-glaucomatous eye. The goals of the studies were to examine penetration and concentration of NB1111 in ocular tissues responsible for IOP regulation and to correlate that concentration to measurement of IOP. Additionally, the studies examined the effect on drug half-life by encapsulating NB1111 in a SLN with single- and multiple-day dosing for up to five days.

The data revealed:

  • NB1111 lowered IOP in a normal eye in a statistically significant manner with peak IOP decline of 32% versus 16% for Pilocarpine and 23% for Timolol (p< 0.05); prior experiments in a glaucomatous eye exhibited a 45% IOP reduction for NB1111
  • The experiments demonstrated that increased drug concentration of NB1111 in the ciliary body and retina/choroid plexus was correlated with a decline in IOP; these ocular organs help regulate IOP
  • Use of Δ9 – THC (parent molecule, non-prodrug), whether formulated in an emulsion or SLN eye drop solution, resulted in no significant tissue concentration nor decline in IOP
  • Formulation of NB1111 into an SLN produced a duration of activity that could be consistent with twice daily eye drop dosing in humans and successfully transported the drug into both the anterior and posterior compartments of the eye and was highly significant compared to both approved comparator drugs (p<0.001)
  • No safety issues were noted with the administration of NB1111 over five days dosing
  • No free THC was detected in the peripheral circulation of the test animals after repeated dosing NB1111 using an assay with nanogram detection sensitivity

“These findings are critical to our understanding on how this novel prodrug of THC can reduce IOP so effectively,” stated Soumyajit Majumdar, PhD, Professor of Pharmaceutics and Drug Delivery and Associate Dean for Research in the School of Pharmacy at the university and lead scientist of the ophthalmic studies of NB1111. “As important as the ocular findings were in these studies, we were also pleased to see that the plasma THC levels in these animals, even those undergoing repeated ocular dosing, did not have detectable levels of THC. This is a key safety finding for this drug.”

Dr. Mahmoud ElSohly, professor at the National Center for Natural Products Research at the University of Mississippi, commented: “Multiple experiments, including previously reported data, have clearly demonstrated a causal relationship between the drug’s tissue concentration and IOP lowering in both normal and glaucomatous eyes. This unique prodrug technology has enhanced treatment concentrations in the eye and could signal a new therapeutic class for the management of glaucoma.”

“NB1111 has performed above expectations in the ability to lower IOP in these animal models. We want to further explore the neuroprotective effects of cannabinoids upon the optic nerve and move the ophthalmology program into human testing. I am also happy to report that our colleagues at the University of Mississippi have been able to develop an early ocular formulation of our CBD analogue, and in doing so, expands our ocular program into a full-fledged ophthalmology platform that could address multiple eye diseases beyond glaucoma, including diseases of the retina,” noted Brian Murphy, MD, MBA, Nemus CEO and Chief Medical Officer.

A link to the abstract on the AAPS website can be found at

Queen’s Researcher Explores Best Treatments for Glaucoma

Researchers at Queen’s University Belfast together with University of St Andrews and Aberdeen have found that the procedure used to remove cataracts is more successful than current standard treatments with laser in treating Primary Angle-Closure Glaucoma – a leading cause of irreversible blindness worldwide.

Professor Azuara-Blanco at the Centre for Public Health at Queen’s led an international trial comparing two treatments for glaucoma – the standard treatment, or ‘laser iridotomy’, which uses a laser to open a tiny hole in the eye to allow fluid to drain away and reduce the increased eye pressure that causes glaucoma; and ‘lens extraction with intraocular lens implantation’, a surgical procedure to remove the eye’s natural lens and replace it with an artificial plastic lens. The surgical technique of lens extraction and replacement with an artificial plastic lens has been used successfully for decades to restore vision in patients’ with cataracts.

The Queen’s-led Effectiveness in Angle-closure Glaucoma of Lens Extraction (EAGLE) study, supported by the EME Programme, an MRC and NIHR partnership, compared the outcomes for 419 patients – 208 of whom received lens extraction treatment and 211 of whom received laser iridotomy. The patients were treated at hospitals in the UK, Singapore, Malaysia, Hong-Kong and Australia,

The results show that at three years, initial clear lens extraction surgery is more effective than standard laser treatment in terms of patient reported health and vision and for lowering eye pressure. Less eye drops are needed to control the glaucoma. Also, balancing costs and benefits, initial clear lens extraction surgery was more efficient for the NHS. The findings have been published in The Lancet Journal earlier this month.

What is glaucoma?

Glaucoma is an age-related and chronic eye disease typically associated with increased eye pressure and progressive optic nerve damage that may lead to blindness if untreated.

According to the World Health Organisation, glaucoma is the leading cause of irreversible blindness, with the current prevalence of 20 million expected to rise to 34 million by 2040, including 5.3 million with blindness.

Although most people with glaucoma do not become blind, many have substantially impaired quality of life due to restricted peripheral vision and the need for long-term treatment.

Primary angle-closure glaucoma
Explaining the condition, Professor Augusto Azuara-Blanco, from the Centre for Public Health at Queen’s, who led the trial, said: “There are two major types of glaucoma, depending on the drainage channels that take the fluid outside the eye: open or closed angle glaucoma. Angle-closure glaucoma is less common but more severe. It is most prevalent among people of East Asian origin, and in the UK it accounts approximately for 2 out of 10 cases of glaucoma.

“In angle-closure glaucoma, the iris (coloured part of the eye) moves forward and blocks the drainage channels that allow fluids to drain away from the eye. When the drainage channels are closed the inner eye pressure increases, and this leads to damage and impaired vision.

“For many years, this has been treated by using lasers to open tiny holes in the iris of the eye and open the drainage channels, allowing fluid to drain away. But we have found that removing the eye’s own lens opens up the natural drainage channels more effectively, and patients are happier because many do not need to use to use glaucoma eye drops and their vision is improved. This surgical technique has been used successfully for years to restore sight in patients with cataracts. Advances in technology and surgical techniques over the past decade mean that it is quite safe and it can now be used to treat people with this type of glaucoma. This trial is the first in which the two treatments have been compared.”

Improved patient outcomes

Professor Azuara-Blanco continued: “Patients who received the lens extraction and implantation were more likely to report better quality of life and better vision. It is also more cost-effective than the current standard treatment. Both options appear to be equally safe.

“Vision loss is costly to individuals and society and can have a huge impact on an individual’s quality of life. The superiority of clear-lens extraction in terms of patient outcomes and cost-saving , along with the absence of any serious safety issues with this technique, should help contribute to a case for this approach to be considered as the initial treatment for people with primary angle-closure glaucoma.”

Microbes In Your Gut Influence Major Eye Disease

Age-related Macular Degeneration (AMD) is the leading cause of irreversible blindness in the industrialized world, affecting over 10 million individuals in North America. A study lead by Dr. Przemyslaw (Mike) Sapieha, researcher at Hôpital Maisonneuve-Rosemont (CIUSSS de l’Est-de-l’Île-de-Montréal) and professor at the University of Montreal, published in EMBO Molecular Medicine, uncovered that bacteria in your intestines may play an important role in determining if you will develop blinding wet AMD.

AMD is characterized by a heightened immune response, sizeable deposits of fat debris at the back of the eye called soft drusen (early AMD), destruction of nerve cells, and growth of new diseased blood vessels (wet AMD, late form). While only accounting for roughly 10% of cases of AMD, wet AMD is the primary form leading to blindness. Current treatments becomes less effective with time. It is therefore important to find new ways to prevent the onset of this debilitating disease.

While many studies on the genetics of AMD have identified several genes that predispose to AMD, no single gene can account for development of the disease. Epidemiological data suggests that in men, overall abdominal obesity is the second most important environmental risk factor, after smoking, for progression to late-stage blinding AMD. Until now, the mechanisms that underscore this observation remained ill defined. Elisabeth Andriessen, a PhD student in the lab of Professor Sapieha found that changes in the bacterial communities of your gut, such as those brought on by a diet rich in fat, can cause long-term low-grade inflammation in your whole body and eventually promote diseases such as wet AMD. Among the series of experiments conducted as part of this study, the group performed fecal transfers from mice receiving regular fat diets, compared to those receiving a high fat diet, and found a significant amelioration of wet AMD.

“Our study suggests that diets rich in fat alter the gut microbiome in a way that aggravates wet AMD, a vascular disease of the aging eye. Influencing the types of microbes that reside in your gut either through diet or by other means may thus affect the chances of developing AMD and progression of this blinding disease”, says Dr Sapieha. Professor Sapieha holds the Wolfe Professorship in Translational Vision Research and a Canada Research Chair in retinal cell biology.

Saving Sight In Glaucoma: Why The Brain May Hold The Key

What causes vision loss in glaucoma? There are two common answers that at first may seem disparate: the first is pressure, as in elevated ocular pressure, and the second is damage to the optic nerve, which is the structure that sends visual information to the brain. Both answers are correct.

Glaucoma involves sensitivity to ocular pressure (not just elevated pressure) that is translated or transduced to stress that degrades the optic nerve over time. Current glaucoma therapies lower pressure using eye drops, surgery, or both in order to reduce stress transduced to the optic nerve. This approach is effective for many patients. But for those who continue to lose vision, where should we turn for new clinical therapies?

One idea is to consider where ocular pressure exerts its influence: the optic nerve head. This structure in the back of the eye defines where nerve fibers leave the retina and enter the optic nerve. The nerve head contains lateral structures that support these fibers but also couple the nerve to the rest of the eye. In this way, pressure in the front of the eye can cause stress to the optic nerve. While we do not understand precisely how this stress is conveyed, we do know that aging of the nerve head is likely to contribute to its susceptibility. By addressing age-related factors, new research might reveal therapies based on reducing the sensitivity of the nerve head to pressure.

What about the optic nerve itself? Like the brain, the optic nerve and retina are part of the central nervous system. Once damaged beyond a certain point, these structures cannot heal. For patients who have lost substantial optic nerve tissue in glaucoma, the hope of regenerative medicine is to restore connectivity with the brain by introducing new nerve fibers or inducing damaged ones to regrow.

Another area of promise that may be forthcoming leverages the idea that increasing brain activity in some cases increases its resistance to stress. Catalyst for a Cure (CFC) research has demonstrated a “window of structural persistence” in which connectivity between the optic nerve and brain remains even when glaucoma affects visual function. During this “window,” optic nerve fibers attempt to boost their electrical activity through natural self-repair mechanisms.

New research by CFC investigators shows that enhanced activity can also help optic nerve fibers regenerate. Perhaps the best approach to a new type of nerve-based glaucoma treatment would combine optic nerve regenerative techniques with those that promote intrinsic repair in the brain.

Promise Of Gene Therapy For Glaucoma Shines Bright In Award-Winning Image

Whether you see the gossamer wings of a butterfly or the delicate opened petals of a flower, there is beauty in the eye of the beholder — a mouse retina described and visually captured by scientists at the National Center for Microscopy and Imaging Research (NCMIR) at University of California San Diego School of Medicine and Shiley Eye Institute at UC San Diego Health.

The confocal microscope image, which depicts a mouse retina sparkling with fluorescent molecules, has been awarded first prize in the National Institutes of Health’s 2016 Combined Federal Campaign “Beauty of Science,” an arts competition to inspire awareness and support of federal scientific efforts.

The image was featured in a study published last year in the journal Cell Death and Disease by UC San Diego School of Medicine and Shiley Eye Institute researchers investigating potential restorative therapies for glaucoma, a progressive disease involving damage to the eye’s optic nerve and irreversible vision loss. An estimated 70 million people worldwide, including 3 million Americans, suffer from glaucoma, though many are unaware and undiagnosed. It is the leading cause of blindness in persons over age 60.

Glaucoma is characterized by the gradual death of neurons called retinal ganglion cells, which transmit light information from the retina to the brain via the optic nerve. “Past research has suggested that targeting these cells with gene therapy designed to prevent their death might slow progression of the disease,” said Robert N. Weinreb, MD, director of both the Hamilton Glaucoma Center and Shiley Eye Institute, and a co-author of the 2015 Cell Death and Disease paper.

Weinreb, with senior author Wonkyu Ju, PhD, associate professor, and colleagues investigated whether a non-disease-causing virus could be used to effectively deliver therapeutic genes to retinal ganglion cells. In the award-winning image, created by Ju, associate project scientist Keunyoung Kim, PhD, and NCMIR director Mark Ellisman, PhD, a virus carrying a gene tagged with green fluorescent protein (GFP) was introduced into the eyes of 7-month-old mice.

Two months later, the retinas were examined using large-scale mosaic confocal microscopy, a technique pioneered at NCMIR with funding support from the National Institute of General Medical Sciences. “It’s similar to Google Earth in that we computationally stitch together many, many small high-resolution images,” said Ellisman, who also directs the Center for Research in Biological Systems, which promotes cross-disciplinary research involving NCMIR, the San Diego Supercomputer Center, the California Institute for Telecommunications and Information Technology and UC San Diego Health Sciences.

In the image, GFP expression (yellow) is observed broadly distributed in all parts of retinal ganglion cells, suggesting the viral delivery system could deliver therapeutic genes. The blue dots indicate Brn3a-positive retinal ganglion cells. Brn3a is a marker for retinal ganglion cells. This was stained for examining transduction efficiency of AAV2-GFP in retinal ganglion cells.

Visual Cortex Plays Role In Plasticity Of Eye Movement Reflex

By peering into the eyes of mice and tracking their ocular movements, researchers made an unexpected discovery: the visual cortex – a region of the brain known to process sensory information – plays a key role in promoting the plasticity of innate, spontaneous eye movements. The study, published in Nature, was led by researchers at the University of California, San Diego (UCSD) and the University of California, San Francisco (UCSF) and funded by the National Eye Institute (NEI), part of the National Institutes of Health.

“This study elegantly shows how analysis of eye movement sheds more light on brain plasticity– an ability that is at the core of the brain’s capacity to adapt and function. More specifically, it shows how the visual cortex continues to surprise and to awe,” said Houmam Araj, Ph.D., a program director at the NEI.

Without our being aware of it, our eyes are in constant motion. As we rotate our heads and as the world around us moves, two ocular reflexes kick in to offset this movement and stabilize images projected onto our retinas, the light-sensitive tissue at the back of our eyes. The optokinetic reflex causes eyes to drift horizontally from side-to-side— for example, as we watch the scenery through a window of a moving train. The vestibulo-ocular reflex adjusts our eye position to offset head movements. Both reflexes are crucial to survival. These mechanisms allow us to see traffic while driving down a bumpy road, or a hawk in flight to see a mouse scurrying for cover.

The two reflexes occur automatically as a result of signals from the brainstem, an evolutionarily older part of the brain. These reflexes also are precisely coordinated in relation to each other. When one of the two reflexes is impaired by age or alcohol, for example, the other compensates. This orchestration requires adaptive plasticity, said the study’s lead investigator, Massimo Scanziani, Ph.D., who at the time of the study was professor of neurobiology at UCSD before moving to UCSF. Scanziani collaborated with the study’s first author, Bao-hua Liu, Ph.D., a post-doc at UCSD and Andrew Huberman, Ph.D., now associate professor at Stanford University.

Scanziani and his colleagues sought to understand the origins of this adaptive plasticity by studying the eye movements in mice before and after disabling their vestibular ocular reflex. In their mouse model, disabling the vestibulo-ocular reflex increases the optokinetic reflex. They measure the increase by holding the mouse’s head still and then presenting the mouse with visual stimuli in the form of black and white horizontal stripes that rotate around the mouse. A camera records the animal’s eye movements. More forceful eye movements indicate an increase in optokinetic reflex activity.

To test the visual cortex’s role in the plasticity of these reflexes, the researchers applied a technique called optogenetics, which uses light to turn target cells on or off. The researchers targeted inhibitory neurons in the visual cortex to turn them “on,” thus silencing that region of the brain. Silencing the visual cortex led to a significant reduction in the activity of the optokinetic reflex, suggesting that it is the visual cortex that is involved in mediating the plasticity between the optokinetic and the vestibulo-ocular reflexes.

Next, the researchers sought to learn more about how the visual cortex modulates the reflexes. It has long been observed that a collection of neural projections from the visual cortex extends to cells of the brainstem that regulate innate motor behaviors. The scientists lesioned these projections and again observed a decrease in the optokinetic reflex. Such findings suggest that the neural projections are the anatomical structures by which the visual cortex adjusts the plasticity of the optokinetic reflex, Scanziani said.

The findings shed new light on the role of the mammalian cortex in orchestrating eye movement, according to Scanziani. “Most of our reflexes are encoded in the brainstem, but from an evolutionary standpoint, the ability for one’s cortex to modify these reflexes expands one’s behavioral repertoire as the circumstances require,” he said. “If you’ve ever noticed how people in an audience tend to cough after a solo musical performance ends, you’ve seen this ability to modify reflexes in action. It’s an ability that appears to have been an attribute important for survival. After all when you’re hiding from a tiger, it would be the very worst moment to cough.”

New Class of Medicinals based on Cannabinoid Molecules, Spurs NEMUS Bioscience Inc. into Action

Q&A with Brian Murphy MD, CEO/CMO, NEMUS Bioscience

Humans produce a range of chemical compounds called cannabinoids that keep the human body stable by binding to receptors on cell membranes and controlling the release of chemical messengers that regulate everything from how humans experience pain to our moods. While most people’s endocannabinoid systems naturally help maintain a state of homeostasis, or stability, conditions such as multiple sclerosis or treatments for diseases like cancer can throw off that balance. Introducing cannabinoids made outside the body might help. Marijuana also contains cannabinoids – at least 66 of them.

Drugs based on cannabinoids, which could treat ailments ranging from arthritis to epilepsy, hold untold potential for the pharmaceutical industry.

The recently spoke with Dr. Brian Murphy, NEMUS Bioscience’s CEO and CMO on the potential of cannabinoid research.

Q: What is NEMUS Bioscience working on?

Murphy: NEMUS Bioscience (OTCQB: NMUS) was formed to bring a new class of medicinals, based on the 100+ cannabinoid molecules in the Cannabis sativa plant, to a variety of therapeutic markets, especially those of unmet medical need.  Almost every organ in the body possesses cannabinoid receptors giving these compounds tremendous versatility in affecting the course of disease.

Q: What are the main diseases or symptoms you are attempting to target with cannabinoid research?

Murphy: The NEMUS developmental pipeline is currently focused on three therapeutic silos:

1) Palliative care addressing specific indications of chemotherapy-induced nausea and vomiting (CINV) and chemotherapy-induced peripheral neuropathy, a particularly severe pain syndrome associated with certain type of cancer chemotherapy.

2) Ophthalmology: the initial therapeutic indication being pursued is glaucoma, with initial animal studies in models of glaucoma exhibiting an average 45% reduction in IOP, exceeding current IOP reduction standards with currently approved medications and those in development using the same models.

3) Anti-infectives: Nemus is developing cannabinoid-based therapeutics against both bacterial and viral targets, with the initial therapeutic target in this silo being methicillin-resistant Staphylococcus aureus (MRSA). The current MRSA epidemic in the United States accounts for close to $4 billion in associated health-care costs as this bacterium has developed resistance to many antibiotics.  Newer therapies are needed.

Q: Describe your partnership with the University of Mississippi and how has the partnership benefited your research?

Murphy: The University of Mississippi (UM) is the only entity in the United States currently licensed by the federal government to grow, cultivate, and research cannabinoids autonomously.  The University has held that license since 1968 and has a tremendous amount of intellectual capital and experience in the chemistry and physiology of cannabinoid molecules.  That library of molecules and associated intellectual property helps distinguishes us from other companies in the cannabinoid therapeutic space.

Q: What difficulties have you encountered working with pharmaceuticals derived from cannabis?

Murphy: While marijuana is not a legal substance, drug companies are permitted to work with and develop derivatives from the plant and develop these molecules into drugs.  Many leading approved medicinals for cardiovascular disease, cancer, and anti-infectives are derived from plants or as is known in pharma development: botanically derived medications.  There is a designated regulatory pathway from both the DEA and FDA for cannabinoids and NEMUS works diligently to be in compliance with those requirements. To-date, we have not experienced any unexpected challenges outside the norm in developing a new class of compounds to address diseases.

Q: What is your opinion on people who smoke/ eat marijuana to relieve painful physical/ mental symptoms? In other words, why are cannabinoids better than the plant itself?

Murphy: For patients who use plant-derived cannabinoids, there are a number of challenges that “pharmaceuticalized” cannabinoids can hope to overcome:

  1. a) with an approved drug, you know what you’re getting- with the plant, random analyses performed by regulatory labs have shown that the advertised content doesn’t always reflect what is in the plant
  2. b) with an approved drug, the cannabinoid is specifically designed to combat a particular disease process both in formulation, route of delivery, and mechanism of action.  With plant-derived treatments, one-route of administration doesn’t always fit all diseases
  3. c) FDA approved medications are covered by insurance reimbursement; plant-derived cannabinoids have historically not been covered by insurance.  A month’s supply of plant-derived cannabinoids can run into the hundreds of dollars versus a $5-$10 monthly copay for FDA approved medications
  4. d) pharmaceuticalized cannabinoids undergo a rigorous testing process (randomized, double-blind, placebo controlled clinical trials),  Plant derived cannabinoids have not undergone this type of rigorous testing and in many cases, rely on anecdotal evidence where bias reporting can creep in; until this type of rigorous testing is conducted in plant-derived cannabinoids, marijuana dispensaries run the risk of violating FTC regulations if they make claims on the efficacy and safety of their products

Q: What has been your biggest success in your research so far?

Murphy: The biggest success has been validating our prodrug design in the molecular engineering of the cannabinoid molecule in animal studies that permit the therapy to enter the body with more predictable bioavailability and steady-state drug concentrations.  These proprietary molecules are designed to optimize safety and efficacy by permitting routes of administration that bypass first-pass metabolism in the liver.  We look forward to upcoming human testing to further validate the potential benefits of this drug design approach.

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